The peroxisome proliferator-activated receptors (PPARs) are members of the steroid/thyroid/retinoid nuclear receptor superfamily of ligand-activated transcription factors. Three subtypes of PPARs have been cloned from the mouse and human, i.e., PPARxcex3 and PPARxcex4. In humans, PPARxcex3 and PPARxcex1 are differentially expressed in organs and tissues (see, Willson et al. J Med. Chem. 43:527-50 (2000)).
Nuclear receptors like PPAR possess DNA binding domains (DBDs) that recognize specific DNA sequences (called response elements) located in the regulatory regions of their target genes (see, Mangelsdorf, et al. Cell 83:835-839 (1995)); Perlmann, et al. Cell 90:391-397 (1997)). Activation of PPARs modulates the expression of genes containing the appropriate respective perixosome proliferator response elements (PPRE) in its promoter region.
In the past, the genes regulated by PPARs were believed to be predominantly associated with lipid and glucose metabolism. Thiazolidinediones, which are a class of oral insulin-sensitizing agents that improve glucose utilization without stimulating insulin release, are selective PPAR agonists. U.S. Pat. No. 4,287,200, discloses certain thiazolidine derivatives having the ability to lower blood glucose levels. In addition, U.S. Pat. No. 4,572,912, discloses thiazolindinedione derivatives having the ability to lower blood lipid and blood glucose levels. These compounds were shown to have the ability to decrease the levels of blood lipid peroxides, blood triglycerides and blood cholesterol. A PPARxcex3 antagonist that inhibits adipocyte differentiation has also been synthesized (see, Oberfield, et al., Proc Natl Acad Sci USA 96:6102-6 (1999)).
However, recent discoveries suggest that the genes regulated by PPAR receptors also play a role in other processes. Binding of ligands to PPARs induce changes in the transcriptional activity of genes that modulate inflammatory processes, angiogenesis, cellular proliferation and differentiation, apoptosis, and the activities of iNOS, MMPases and TIMPs. These findings suggest that regulation of the action of PPAR may have a therapeutic role in treating diseases such as occlusive vascular diseases (e.g. atherosclerosis), hypertension, neovascular diseases (e.g. diabetic retinopathy), inflammatory diseases (e.g. inflammatory bowel disease and psoriasis), and neoplastic diseases (carcinogenesis).
The precise contribution of each particular PPAR subtype to transcriptional activation of particular genes is difficult to predict. DNA response elements for both PPARxcex1 and PPARxcex3 have been found in the promoter regions of a variety of genes, including a number involved in lipid and fatty acid metabolism. For example, in fetal rat brown adipocytes, expression of the uncoupling proteins UCP-1, UCP-2 and UCP-3 is controlled via both PPARxcex1 and PPARxcex3 activation. Activation of PPARxcex3 elicited 5- and 3-fold increases in UCP-1 and UCP-3, respectively. In contrast, activation of PPARxcex1 increased UCP-1 ten-fold, but decreased UCP-3. Interestingly, when both PPAR and were activated, a synergistic interaction occurred in regulation of UCP-3.
These differential and synergistic effects may be mediated by co-activator recruitment, suppression of co-repressor proteins, or direct interaction at the level of the PPRE (see, Teruel, et al. Biochem Biophys Res Commun. 273(2):560-4 (2000)). It is not known whether the nuclear receptor coactivators or corepressors identified to date are selective for particular PPAR receptors (see, Spiegelman, et al., Diabetes 47:507-514 (1998)). Many coactivators or corepressors have multiple modes of action and hence it is not clear which cofactors are more important for the function of any particular receptor (see, Puigserver, et al. Science 286:1368-1371 (1999). Furthermore, the tremendous specificity of biological actions of the individual nuclear receptors (see, Spiegelman, et al. Diabetes 47:507-514 (1998)), strongly suggests that the full spectrum of nuclear cofactors that regulate the transcriptional activity of PPARxcex3 and/or PPARxcex1 remains to be defined.
Due to this lack of understanding of PPARxcex3 and PPARxcex1-related activity and mechanisms, as well as the differential expression of PPARxcex3 and PPARxcex1 in cells, it is difficult to ascertain the potential effects of concurrent activation of PPAR gamma and alpha receptors on both cellular processes relevant to disease. For example, PPARxcex1 or PPARxcex3 may either have similar or disparate effects. It is known that inflammatory activation of human aortic smooth-muscle cells is inhibited by PPARxcex1, but not by PPARxcex3. Apoptosis in human monocyte-derived macrophages is induced by activation of either PPARxcex1 and PPARxcex3 (see, Staels et al. Nature 393:790-3 (1998)); Chinetti, et al. J Biol Chem. 273:25573-80 (1998)). However, PPARxcex3 activation by troglitazone or 15-deoxy-xcex94-12-14-prostaglandin J2 protects cerebellar granule cells from cytokine-induced apoptotic cell death (see, Heneka, et al. J Neuroimmunol 100:156-68 (1999)).
To summarize, PPAR subtypes exhibit differential patterns of tissue expression, different actions on different response elements, differential effects on co-activators and co-repressors, and differential regulation of access to the core transcriptional machinery. This complexity of PPAR regulation makes it extremely difficult to predict precisely which genes will ultimately be activated (transcribed) or inactivated (suppressed) as a result of activation by a particular combination of an agonist or an antagonist of PPARxcex3 or PPARxcex1. As a consequence, it is impossible to predict with certainty the way in which a tissue expressing PPARxcex3 and PPARxcex1 may respond to a particular ligand, or whether a particular pathological state will be attenuated, arrested, accentuated or worsened by said ligand. This is especially the case in which a single ligand activates both PPARxcex3 and PPARxcex1 to similar degrees.
In view of this complex interplay between PPARxcex3 and PPARxcex1, it is desirable to synthesize compounds, which bind both receptors and can take advantage of potential synergistic effects. For example, PPARxcex3 and PPARxcex1 activation has been shown to inhibit proliferation (see, Ellis, et al. Arch Dermatol. 136:609-616 (2000)) and promote differentiation of epidermal keratinocytes, respectively (see, Komuves et al. J Invest Dermatol. 115:353-360 (2000)).
The syntheses of thiazolidine dithiolane derivatives with affinity for PPARxcex3 have been described in WO 00/53601, published Sep. 14, 2000. Despite the advances of WO 00/53601, what is needed in the art are non-thiazolidinedione (non-TZD) dithiolane derivatives with high affinity for PPARxcex3 that function either as PPARxcex3 agonists, PPARxcex3 antagonists, or mixed PPARxcex3 agonist/antagonists. Methods to synthesize these non-TZD compounds with high affinity for both PPARxcex3 and PPARxcex4, antagonists, mixed (partial) agonist/antagonists, or mixed PPARxcex3/PPARxcex4 agonists are also needed. The present invention remedies such needs.
The present invention provides novel dithiolane derivatives which can be used to ameliorate PPARxcex3-mediated diseases such as inflammatory and proliferative diseases and those that are characterized by inappropriate activation of nuclear transcription factors.
As such, in one embodiment, the present invention provides compounds of Formula A: 
In Formula A, R is a functional group including, but not limited to R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl); R or S or racemic S,Sxe2x80x2-Diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,Sxe2x80x2-Diacyl-[2-(1,3-dithiopropanyl)]; and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl (or also named as a 3H-benzo[1,2]dithiol-6-yl) moieties. The term xe2x80x9cdiacylxe2x80x9d as used herein means the either one sulfur or both sulfurs are substituted with an acyl group. In a preferred embodiment, the xe2x80x9cdiacyl groupxe2x80x9d are amino acid derivatives and thus, the compounds of Formula A are soluble in aqueous solution.
R1, in Formula A, is a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl.
R11, in Formula A, is a functional group including, but not limited to R, S or racemicxe2x80x94CH2(Z)CHCO2R2, xe2x80x94CH2CO2R12, xe2x80x94CO2R . R is a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl.
A, in Formula A, is oxygen or, in an alternative embodiment, A, together with the carbon to which it is bound is a methylene group.
B, in Formula A, is a functional group including, but not limited to, N, O and S, provided that when B is O or S then R1 is absent.
X, in Formula A, is a functional group including, but not limited to, hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3. R3 and R10 are each independently functional groups including, but not limited to hydrogen, alkyl, arylalkyl and aryl.
Y, in Formula A, is a functional group including, but not limited to oxygen, S, SO, SO2, SO2NH, SO2NR12, SO3, NH, NR12. R12 is a functional group including, but not limited to hydrogen, alkyl, arylalkyl and aryl.
Z, in Formula A, is a functional group including, but not limited to, R S-phenyl, S S-phenyl, racemic S-phenyl, SCH3, SCH2CH3, O-phenyl, OCH3, SCH2CH3, propyl, butyl, pentyl, hexyl, benzyl, haloalkyl, NHR13, NR13R14. R13 and R14 are each independently functional groups including, but not limited to, xe2x80x94(CO)alkyl, optionally substituted xe2x80x94(CO)aryl, optionally substituted xe2x80x94(CO)arylalkyl, optionally substituted xe2x80x94(CO)heteroaryl and xe2x80x94CHO.
In Formula A, in the index xe2x80x9cmxe2x80x9d is an integer from 1 to 8 inclusive, r is 0 or 1; n is 0,2,3,4; and p is 0 or 1.
In Formula A, when n is 0 then Y is not O, S, N, as this would result in N-O, N-S, and N-N bonds.
Formula I, II, IV, and V are preferred embodiments of Formula A.
In another embodiment, the present invention provides compounds of Formula 
In Formula I, R is a functional group including, but not limited to R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl); R or S or racemic S,Sxe2x80x2-Diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,Sxe2x80x2-Diacyl-[2-(1,3-dithiopropanyl)]; and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl (or also named as a 3H-benzo[1,2]dithiol-6-yl) moieties.
R1, in Formula I, is a functional group including, but not limited to hydrogen, alkyl, arylalkyl and aryl.
R2, in Formula I, is a functional group including, but not limited to hydrogen, alkyl, arylalkyl and aryl.
A, in Formula I, is oxygen or, in an alternative embodiment, A, together with the carbon to which it is bound is a methylene group.
X, in Formula I, is a functional group including, but not limited to, hydrogen, halogen, OR3, NH2 NHR3, NR3 R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3. R3 and R10 are each independently functional groups including, but not limited to, hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cXxe2x80x9d is meta to the fixed functional group, i.e., the group comprising xe2x80x9cZxe2x80x9d.
Y, in Formula I, is a functional group including, but not limited to, oxygen, S, SO, SO2, SO2NH, SO2NR3, SO3, NH, NR3. R3, in Formula I, is a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cYxe2x80x9d is para to the fixed functional group, i.e., the group comprising xe2x80x9cZxe2x80x9d.
Z, in Formula I, is a functional group including, but not limited to, R S-phenyl, S S-phenyl, racemic S-phenyl, SCH3, SCH2CH3, O-phenyl, OCH3, SCH2CH3, propyl, butyl, pentyl, hexyl, benzyl and haloalkyl.
In Formula I, the index xe2x80x9cmxe2x80x9d is an integer from 1 to 8 inclusive.
In Formula I, the index xe2x80x9cnxe2x80x9d is 0, 2, 3, 4 and the index xe2x80x9cpxe2x80x9d is 0 or 1.
In Formula I, when n is 0 then Y is not O, S, N, as this would result in Nxe2x80x94O, Nxe2x80x94S, and Nxe2x80x94N bonds.
In another embodiment, the present invention provides a compound of Formula II: 
In Formula II, R is a functional group including, but not limited to, R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl); R or S or racemic S,Sxe2x80x2-Diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,Sxe2x80x2-Diacyl-[2-(1,3-dithiopropanyl)]; and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl (or also named as a 3H-benzo[1,2]dithiol-6-yl) moieties.
R1, in Formula II, is a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl.
R2, in Formula II, is a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl.
A, in Formula II, is oxygen or, in an alternative embodiment, A, together with the carbon to which it is bound is a methylene group.
X, in Formula II, is a functional group including, but not limited to, hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3. R3 and R10, are each independently functional groups including, but not limited to hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cXxe2x80x9d is meta to the fixed functional group, i.e., the group comprising xe2x80x9cZxe2x80x9d.
Y, in Formula II, is a functional group including, but not limited to, oxygen, S, SO, SO2, SO2NH, SO2NR3, SO3, NH, NR3. R3 is a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cYxe2x80x9d is para to the fixed functional group, i.e., the group comprising xe2x80x9cZxe2x80x9d.
Z, in Formula II, is a functional group including, but not limited to, R S-phenyl, S S-phenyl, racemic S-phenyl, SCH3, SCH2CH3, O-phenyl, OCH3, SCH2CH3, propyl, butyl, pentyl, hexyl, benzyl and haloalkyl.
In Formula II, the index xe2x80x9cmxe2x80x9d is an integer from 1 to 8 inclusive, the index xe2x80x9cnxe2x80x9d is 0, 2, 3 or 4; and the index xe2x80x9cpxe2x80x9d is 0 or 1. In Formula II, when n is 0 then Y is not O, S, N, as this would result in Nxe2x80x94O, Nxe2x80x94S, and Nxe2x80x94N bonds.
In yet another embodiment, the present invention provides a compound of Formula III: 
In Formula III, R is a functional group including, but not limited to, R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl); R or S or racemic S,Sxe2x80x2-Diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,Sxe2x80x2-Diacyl-[2-(1,3-dithiopropanyl)]; and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl (or also named as a 3H-benzo[1,2]dithiol-6-yl) moieties.
R1, in Formula III, is a functional group including, but not limited to hydrogen, alkyl, arylalkyl and aryl.
R2, in Formula III, is a functional group including, but not limited to hydrogen, alkyl, arylalkyl, and aryl.
R4, in Formula III, is a functional group including, but not limited to hydrogen and alkyl.
A, in Formula III, is a member selected from the group consisting of oxygen or, in an alternate embodiment, A, together with the carbon to which it is bound is a methylene group.
X, in Formula III, is a functional group including, but not limited to hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3. R3 and R10 are each independently a functional group consisting of hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cXxe2x80x9d is meta to the fixed functional group, i.e., the group comprising xe2x80x9cR4xe2x80x9d.
Y, in Formula III, is a functional group including, but not limited to oxygen, S, SO, SO2, SO2NH, SO2NR3, SO3, NH, NR3, wherein R3 is a functional group including, but not limited to hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cYxe2x80x9d is para to the fixed functional group, i.e., the group comprising xe2x80x9cR4xe2x80x9d.
In Formula III, the index xe2x80x9ctxe2x80x9d is an integer from 1 to 5 inclusive; the index xe2x80x9cvxe2x80x9d is an integer from 2 to 8 inclusive; and the index xe2x80x9cyxe2x80x9d is an integer from 2 to 4 inclusive; and the index xe2x80x9cpxe2x80x9d is 0 or 1.
In still yet another embodiment, the present invention provides a compound of Formula IV: 
In Formula IV, R is a functional group including, but not limited to R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl); R or S or racemic S,Sxe2x80x2-Diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,Sxe2x80x2-Diacyl-[2-(1,3-dithiopropanyl)]; and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl (or also named as a 3H-benzo[1,2]dithiol-6-yl) moieties.
R1, in Formula IV, is a functional group, including, but not limited to, hydrogen, alkyl, arylalkyl and aryl.
R4, in Formula IV, is a functional group including, but not limited to, hydrogen and alkyl.
A, in Formula IV, is oxygen or together with the carbon to which it is bound is a methylene group.
X, in Formula IV, is a functional group including, but not limited to, hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3. R3 and R10 are each independently functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cXxe2x80x9d is meta to the fixed functional group, i.e., the group comprising xe2x80x9cR4xe2x80x9d.
Y, in Formula IV, is a fuinctional group including, but not limited to, oxygen, S, SO, SO2, SO2NH, SO2NR3, SO3, NH, NR3, wherein R3, is a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl. In Formula IV, the index xe2x80x9cmxe2x80x9d is an integer from 1 to 8 inclusive; the index xe2x80x9cnxe2x80x9d is 0, 2, 3 or 4; and the index xe2x80x9cpxe2x80x9d0 is 0 or 1. In Formula IV, when n is 0 then Y is not O, S, N, as this would result in Nxe2x80x94O, Nxe2x80x94S, and Nxe2x80x94N bonds. In a preferred embodiment, xe2x80x9cYxe2x80x9d is para to the fixed functional group, i.e., the group comprising xe2x80x9cR4xe2x80x9d.
In still yet another embodiment, the present invention provides a compound of Formula V: 
In Formula V, R5 and R6 are each independently functional groups including, but not limited to, hydrogen, alkyl, arylalkyl and aryl, and where C-3 is either R, S, racemic or achiral.
R7, in Formula V, is a functional group including, but not limited to, hydrogen and alkyl.
R8, in Formula V, is a functional group including, but not limited to, hydrogen and alkyl or is absent.
In an alternative aspect, R7 and R8 and the atoms to which they are bound, join to form a 5-, or 6-membered aryl or heteroaryl ring.
R9, in Formula V, is a functional group including, but not limited to, hydrogen and alkyl.
Q, in Formula V, is a functional group including, but not limited to, O, S, NH and NCH3.
X, in Formula V, is a functional group including, but not limited to, hydrogen, halogen, OR3, NH2, NHR3, NR3R10, SR3, SOR3, SONH2, SONHR3, SO2NH2, SO2R3, SO2NHR3 and SO3R3. R3 and R10 are each independently a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cXxe2x80x9d is meta to the fixed functional group, i.e., the group comprising xe2x80x9cR9xe2x80x9d.
Y, in Formula V, is a functional group including, but not limited to, oxygen, S, SO, SO2, SO2NH, SO2NR1, SO3, NH, NR3. R3 is a functional group including, but not limited to, hydrogen, alkyl, arylalkyl and aryl. In a preferred embodiment, xe2x80x9cYxe2x80x9d is para to the fixed functional group, i.e., the group comprising xe2x80x9cR9xe2x80x9d.
In Formula V, the index xe2x80x9cwxe2x80x9d is an integer from 2 to 6 inclusive; and the index xe2x80x9cpxe2x80x9d is 0 or 1.
In other aspects, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier.
In another aspect, the present invention relates to a method of treating a PPARxcex3 mediated disease or oxidative stress, comprising administering a therapeutically effective amount of a compound of the present invention or mixtures thereof to an individual suffering from a PPARxcex3-mediated disease.
In other aspects, this invention provides methods for synthesizing the compounds of Formula A I, II, III, IV, and V. These and other aspects and advantages will become more apparent hen read with the detailed description and drawings which follow.